With the development of the society, people's living standard is continuously improved and dietary is adjusted. Diet has a trend of surplus growth, which leads to an increase morbidity rate of metabolic diseases. Wherein, most remarkable diseases are hyperglycaemia and hyperlipidemia. Until now, the number of the world's diabetic patients is about 200 million, and the amount is increasing every year with surprising speed. Besides, morbidity rate of atherosclerosis, coronary disease or other angiocardiopathy caused by the rise of blood lipid has increased year by year, and there is a younger trend in the angiocardiopathy. Drugs using in decreasing blood glucose and blood lipid have been one of the important projects in drugs research.
In recent years, successful development of HMG-CoA reductase inhibitors becomes a breakthrough in the studies of lipid-lowering drugs. These drugs, which have good therapeutic effects in treating hypercholesterolemia, can inhibit rate-limiting enzyme (i.e. HMG-CoA reductase) in cholesterol synthesis through competitive inhibition, thus decreasing the level of endogenous cholesterol synthesis.
α-glucosidase, including α-amylase, maltase, isomaltase, sucrase, lactase, trehalase and so on, is a series of hydrolase locating on intestinal villi brush border membrane and mainly participates in body's digestion and absorption of carbohydrate. A-glucosidase inhibitor, a first-line glucose-lowering drug for treating type II diabetics when simply diet control is invalid, can inhibit α-glucosidase on intestinal villi brush border through competitive inhibition or non-competitive inhibition, and delay the process of oligosaccharide or polysaccharide converted into absorbable monosaccharide, thus effectively inhibiting the increase of postprandial blood glucose of diabetics and maintaining blood glucose within the desired range smoothly and slowly.
The main α-glucosidase inhibitors in market include acarbose, voglibose, migltol and so on. It's remarkable that these inhibitors have severe toxic side effects in various degrees, such as gastrointestinal side effects, urticaria, hepatosis and angiocardiopathy risk.
Therefore, it is necessary and urgent to develop a more secure and powerful drug for preventing and treating hyperglycaemia and hyperlipidemia.
Type II occupies the majority in diabetics. Insulin resistance is the key causative factor of type II diabetics and protein tyrosine phosphatase 1B (PTP1B) also plays a key role in the formulation of insulin resistance. Studies have shown that PTP1B, a negative regulator of insulin signal pathway, can dephosphorylate the tyrosine residues both in activated insulin receptors and substrate thereof, thus terminating insulin signal pathway and causing body's insulin resistance and relative insulin deficiency, and finally developing into diabetes type II. Animal research has shown that the insulin sensitivity of PTP1B knockout mouse raises significantly in glucose tolerance and insulin tolerance test. Therefore, PTP1B inhibitor may be considered as a drug which plays an important role in glucose-lowering.
In recent years, as a new direction in treating diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitors have attracted widespread attention of medicinal chemists. In 2006, Merck's sitagliptin has been approved by FDA for marketing as the first DPP-4 inhibitor. Dipeptidyl peptidase-4 (DPP-4) is a kind of serine proteinase which can rapidly cleave and inactivated incretin such as GLP-1 and GIP. As a multipurpose proteolytic enzyme, DPP-4 inhibitors can inhibit the degradation of GLP-1 and GIP, enhance the activity of incretin and neuropeptide, decrease the fasting or postprandial glucose concentration and glycosylated hemoglobin levels, and improve the insulin sensitivity and β cell function.
The hyperfunction of polyols metabolic activity is one of the contributing factors of diabetic complication. With the increase of blood sugar, hexokinase used for catalysing glucose changing into glucose-6-phosphate is saturated, which stimulates the generation of aldose reductase (AR), thus increasing the activity of AR and activate the sorbitol pathway. Due to its polarity, sorbitol is hard to go through the cell membrane. A large amount of sorbitol is produced in cells, which may cause diabetic complication such as diabetic nephropathy, vasculopathy and retinopathy. Aldose reductase inhibitor can inhibit the AR in polyol pathway and prevent the glucose changing into sorbitol, then polyols' level returns to normal, nerve conduct function is improved, and the formation of cataract and the appearance of albuminuria can be delayed, thus achieving the aim of preventing and delaying diabetic complication.